GLP-1 and dual GIP/GLP-1 agonists in obese patients with HFpEF: a systematic review and meta-analysis of RCTs.

BACKGROUND: Obesity-related heart failure with preserved ejection fraction (HFpEF) is characterized by impaired exercise tolerance and poor health status. Metabolic modulation using glucagon-like peptide-1 (GLP-1) receptor agonists and dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 agonists has emerged as a potential therapeutic strategy. OBJECTIVES: To evaluate effects of GLP-1 and GIP/GLP-1 agonists on heart failure hospitalization, symptoms, physical function, body weight, and mortality in patients with HFpEF and obesity. METHODS: We searched MEDLINE, CENTRAL, and ClinicalTrials.gov through November 2025 for randomized controlled trials enrolling adults with HFpEF (left ventricular ejection fraction ≥ 45%) and obesity (body mass index ≥ 30 kg/m², or ≥ 27 kg/m² with at least one obesity-related comorbidity) treated with GLP-1 or GLP-1/GIP agonists. Primary outcome was first heart failure hospitalization. Secondary outcomes included Kansas City Cardiomyopathy Questionnaire Clinical Summary Score, six-minute walk distance, percentage bodyweight change, and all-cause mortality. RESULTS: Four trials ( = 4,149) met criteria. Two trials contributed adjudicated first heart failure hospitalization, demonstrating pooled hazard ratio 0.52 (95% confidence interval 0.33–0.82). Incretin therapy improved Kansas City Cardiomyopathy Questionnaire by 7.4 (95% CI 4.9–9.9) points and six-minute walk distance by 17.6 m (95% CI 10.7–24.5). Body weight decreased by -9.6% (95% CI -11.3 to -8.0). All-cause mortality did not differ significantly (hazard ratio 0.90, 95% confidence interval 0.67–1.22); however, given the limited number of events across available trials, this finding should be interpreted as inconclusive rather than indicative of a null mortality effect. CONCLUSIONS: GLP-1-based and dual GIP/GLP-1 therapies improve symptoms, physical function, and weight and reduce heart failure events in adults with obesity-associated HFpEF, supporting metabolic modulation as a therapeutic approach. TRIAL REGISTRATION: Systematic review registration: CRD420251237462. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12872-026-05808-7.